Fumarate drugs rescue cardiac dysfunction in mouse models of Friedreich's ataxia

富马酸盐药物可挽救弗里德赖希共济失调小鼠模型的心功能障碍

• 批准号: 10320787
• 负责人: Elena N. Dedkova
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320787
• 关键词: Aconitate Hydratase; Address; Affect; Age; Animals; Ataxia; Biochemical; Biogenesis; Biological Assay; Body Weight decreased; Cardiac; Cardiac Output; Cardiomyopathies; Cell Death; Cessation of life; Clinical Data; Clinical Trials; Complex; Data; Defect; Development; Dose; Drug Kinetics; Drug usage; EFRAC; Enzymes; Equilibrium; FDA approved; Fibroblasts; Fibrosis; Freezing; Friedreich Ataxia; Fumarates; Gender; Hand Strength; Heart; Heart Abnormalities; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histopathology; Human; Impairment; Inherited; Iron; Knockout Mice; Left; Left Ventricular Hypertrophy; Libraries; Longevity; Mediating; Mitochondria; Mitochondrial Proteins; Multiple Sclerosis; Mus; Muscle Mitochondria; Muscle function; Myocardial dysfunction; Myocardium; Myopathy; Necrosis; Neurologic Deficit; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Prodrugs; Proteomics; Psoriasis; Reaction Time; Recovery of Function; Role; Rotarod Performance Test; Safety; Sampling; Sensory; Signal Pathway; Skeletal Muscle; Stroke Volume; Succinate Dehydrogenase; Sulfur; Survival Analysis; Symptoms; Testing; Thick; Time; Tissues; Toxicology; Two-Dimensional Echocardiography; Ventricular; Weight; Wheelchairs; Work; base; cardioprotection; design; drug testing; efficacy testing; enzyme activity; frataxin; heart function; improved; in vivo; knock-down; mortality; mouse development; mouse model; multiple sclerosis treatment; mutant; novel therapeutic intervention; phase 1 study; pre-clinical; prevent; sex

Friedreich's Ataxia (FA) is the most common inherited recessive ataxia, for which there is no FDA-approved therapy. FA's pathophysiological mechanism is caused by the reduction of just one mitochondrial protein, frataxin (FXN), that functions in iron-sulfur (Fe-S) cluster biogenesis. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. Although sensory and balance deficits put FA patients in wheelchairs, nearly all FA patients die of cardiomyopathy. Currently, there are no drug therapies that ameliorate FA cardiomyopathy and most with FA die of the cardiomyopathy in their 30s. We identified redox deficiency in FA human fibroblasts, and used this to screen a library of 1600 drugs already safely used in humans, to test for their ability to prevent cell death in FA. We identified dimethyl fumarate (DMF), a prodrug precursor of monomethyl fumarate (MMF), as the most protective among all tested drugs. DMF (also known as Tecfidera and Skilarence) is the FDA approved drug for treatment of multiple sclerosis (MS) and psoriasis. In the most physiological mouse model of FA (the FXNKD), we found that 1) DMF dose-dependently rescued FXN levels and the mitochondrial Fe-S cluster enzymes aconitase and succinate dehydrogenase activity in the heart; 2) DMF significantly rescued three critical cardiac deficits in mice that resemble human FA cardiac defects: a) left ventricular hypertrophy; b) decreased stroke volume; and c) decreased cardiac output. Preliminary data support the claim that DMF is providing mitochondrial->frataxin-> Fe-S cluster support via Nrf2-dependent mechanism. Additionally, we recently synthesized an alternative MMF prodrug called IMF, with improved pharmacokinetics that may be even more potent than DMF. Therefore, we hypothesize that fumarates DMF/IMF represent a novel therapeutic strategy that can potentially be repurposed for the lethal cardiomyopathy in FA. The aim of the current work is to determine the effects of DMF/IMF on the function of most affected tissues in FA (heart and skeletal muscles), and to determine the mechanism of protective action. DMF has already passed through FDA's safety, toxicology and DMPK hurdles, and thus could enter clinical trials much more quickly than a new compound that must pass through extensive safety and toxicology testing before it could be used in clinical trials. However, before attempting to use the drug in humans with FA, completion of the 'pre-clinical package' for DMF/IMF and their role for cardiac/skeletal muscle protection in FA are important, and can be addressed in the three Specific Aims. Aim 1 is designed to determine optimal dosing of DMF & IMF that rescue cardiac and skeletal muscles deficits. Aim 2 is designed to determine the mechanism responsible for functional recovery in the FXNKD mouse. Aim 3 is designed to determine whether optimal dosing of DMF/IMF extends the life span of mouse with cardiac-specific FXN KO (MCK-Cre). Cumulatively these aims will generate pre-clinical data for the potential use of DMF and IMF for lethal cardiomyopathy in FA. Because DMF is already approved for use in humans with safety/DMPK/toxicology and Phase I studies already completed, it has a greater opportunity to be 'fast-tracked' for treatment of cardiac myopathy in FA.

弗里德赖希共济失调症（FA）是最常见的遗传性隐性共济失调症，目前尚无fda批准的治疗方法